Use dependent forms of synaptic plasticity are likely to be important for essential brain functions such as the formation of memory traces. A short-term form of plasticity that has been extensively studied in this context is homosynaptic facilitation. Homosynaptic facilitation is present in the hippocampus, a structure that is essentia for at least some types of memory tasks. Recently, however it has become apparent that there is a second form of short-term plasticity also present at hippocampal synapses. This type of plasticity is manifested as a graded, potentiating effect of a depolarizing change in membrane potential on synaptic transmission. An important question that has not been addressed is, How do effects of holding potential and homosynaptic facilitation work together to impact the efficacy of synaptic transmission under physiologically relevant conditions? We have begun to address this issue in an experimentally advantageous model system. Somewhat surprisingly we have found that changes in holding potential are relatively ineffective at potentiating synaptic transmission when neurons are activated at frequencies that are too low to induce homosynaptic facilitation. At higher stimulation frequencies, however, holding potential significantly modifies the dynamics of facilitation, i.e., increases its rate of induction. Our research therefore presents a novel view of an important form of short-term synaptic plasticity. Proposed experiments are divided into two aims. The first aim will test a specific hypothesis concerning how effects of holding potential are mediated. A goal of this work will be to determine why holding potential most effectively modifies synaptic transmission when facilitation is induced. The second aim will determine when and why the dynamics of facilitation are modified by changes in membrane potential. Further we will determine how information transfer is impacted. Our research is broadly relevant in that it will identify and characterize a physiologically relevant mechanism that can regulate the dynamics of a form of plasticity (facilitation) that is present in the hippocampus, a structure that plays an important role in learning and memory. Alterations in plasticity, often measured as changes in paired pulse facilitation (PPF), are observed in animal models of a number of pathological conditions including schizophrenia and behavioral anxiety. Further, PPF can be disrupted during acute stress. Thus, correlative data strongly implicate facilitation and its modification as an important determinant of normal brain function. Studies such as ours that will investigate physiological consequences of this type of regulation will indicate why this is so. PUBLIC HEALTH RELEVANCE: An important goal of this research is to study a form of plasticity that is not well understood in which subthreshold changes in membrane potential modify the efficacy of synaptic transmission. In the mammalian brain this occurs under pathological conditions during epileptic seizures, and under normal conditions when synchronized oscillatory activity is generated (e.g., theta rhythms in the hippocampus and up-down states in the cortex). Our research will determine how and why this oscillatory activity modifies synaptic transmission.